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Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 869

response rates are observed when carfilzomib is used in combination glove” distribution, and is frequently painful. Grade ≥3 PN occurs
with other agents such as lenalidomide and low-dose dexamethasone. in 5%–15% of patients but is reversible in the most cases (in the
2
The current FDA-approved dose of carfilzomib is 20 mg/m for cycle phase III VISTA trial, 60% of instances of neuropathy showed
2
1, and 27 mg/m for cycle 2. Recent data have shown MTD of complete resolution within a median of 5.7 months). The mechanism
carfilzomib is higher; therefore, a phase II study is underway to by which bortezomib produces peripheral neuropathy is unknown,
compare the two different doses of carfilzomib in combination with but is hypothesized to be due to aggresome formation and cytoskeletal
dexamethasone in a randomized fashion to determine if a higher dose collapse in dorsal root ganglion sensory neuron axons, alterations in
can improve the efficacy while maintaining a safe toxicity profile. mitochondrial function, or other off-target effects. It is possible that
Oprozomib (ONX-0912): Oprozomib is a structural analog of the boron moiety is implicated in the peripheral neuropathy since
carfilzomib that is orally bioavailable. Oprozomib had demonstrated carfilzomib (which does not contain a boron atom) is much less likely
clinical activity in a phase I trial in patients with hematologic malig- to cause neuropathy than bortezomib. The incidence of peripheral
nancies (myeloma and CLL). A once-daily administered oral dose was neuropathy with bortezomib is reduced by subcutaneous (SC)
introduced in a phase Ib/II trial in order to improve gastrointestinal administration and weekly dosing. The lower incidence of neuropathy
tolerability, and is demonstrating a good safety profile and promising of SC vs. IV administration of bortezomib has been attributed to IV
preliminary response data. dosing achieving peak serum levels of bortezomib that exceed the
Ixazomib (MLN9708): Ixazomib is a boronic acid-containing threshold that causes peripheral neuropathy, whereas the slower
peptide with chymotrypsin- and caspase-like proteasome inhibitory pharmacokinetics of SC administration deliver an effective antimy-
activity, formulated for oral administration. Clinical trials, as single eloma dose without exceeding the neuropathy threshold.
agent and in combination with HDAC inhibitors (HDIs), are
underway to assess its effects in bortezomib-refractory patients. Early Hematologic Toxicity
indications suggest that ixazomib may be associated with less neu- Hematologic adverse events appear to be a class effect associated with
ropathy than bortezomib. proteasome inhibitors; all agents tested so far are associated with
Delanzomib (CEP-18770): Delanzomib is a boronic acid- thrombocytopenia, neutropenia, anemia, and lymphopenia. Differ-
containing peptide formulated for oral administration. Early indica- ences in the tendency of the different agents to cause hematologic toxic-
tions suggest that delanzomib may be associated with less neuropathy ity remain to be established as newer agents undergo further testing in
than bortezomib but it was noted to cause rash. A phase II trial of clinical trials (there is hope that second-generation drugs may have
this drug has been terminated due to lack of efficacy in relapsed/ lower rates of hematologic toxicity). Bortezomib, carfilzomib, and
refractory myeloma patients. ixazomib cause transient, cyclical thrombocytopenia, with platelet
Marizomib (NPI-0052): Marizomib is a novel nonpeptidic, orally counts dropping and then returning to baseline prior to the next cycle
active, irreversibly-binding proteasome inhibitor with broad activity of treatment. The exact mechanism of bortezomib-induced thrombo-
at all three catalytic sites of the proteasome. Since it is not peptide cytopenia remains to be fully elucidated. Bortezomib does not appear
based, marizomib is resistant to degradation by endogenous proteases. to adversely affect stem cell function. One hypothesis is that protea-
It is capable of overcoming bortezomib resistance in vitro; clinical some inhibition with bortezomib prevents the activation of NFκB,
trials are underway but are still in early stages. Dose-limiting toxicities which leads to impairment of platelet budding from megakaryocytes.
in phase I trials have included cognitive changes, transient hallucina-
tions, and loss of balance, which were reversible. The most common Herpes Zoster Reactivation
drug-related adverse effects included fatigue, gastrointestinal adverse Bortezomib has been associated with a significantly increased rate of
events, dizziness, and headache. There was no evidence of neuropathy herpes zoster reactivation. In the phase III study of bortezomib plus
or thrombocytopenia. Since marizomib has a different mechanism of melphalan and prednisone versus MP alone, zoster reactivation was
action from bortezomib, and a nonoverlapping toxicity profile, observed in 13% of patients in the VMP group versus 4% in the MP
combinations of these agents may be evaluated in future studies. group. In the subgroup of patients in the VMP group who were
This is a very active area of research; there are over 10 structurally receiving antiviral prophylaxis, the rate of zoster reactivation was
distinct classes of proteasome inhibitors in development, with new reduced to 3%. The increased susceptibility to herpes zoster reactiva-
agents expected to enter clinical testing in the hopes of finding drugs tion in patients treated with bortezomib may be due to the effect of
with optimal potency, reduced toxicity and oral bioavailability. Table bortezomib treatment on the number and function of specific lym-
57.2 outlines some of the ongoing clinical trials investigating the phocyte subsets.
combination of second-generation proteasome inhibitors with other
agents. Other Toxicities
Infusion reactions (chills, fever, and dyspnea) have been observed
with carfilzomib. Therefore, it is recommended that dexamethasone
Toxicities of Proteasome Inhibitors (4 mg PO or IV) be administered prior to each dose during cycle 1
and prior to the first of the higher doses during cycle 2. Carfilzomib
Given their broad application, prolonged exposure, and use in has been associated with pulmonary complications, renal toxicity, and
combination with other agents with similar toxicities (especially vinca cardiac events (including congestive heart failure and cardiac arrest)
alkaloids and IMiDs), there has been a considerable effort to charac- in 7% of treated patients. Chest pain and acute congestive heart
terize and mitigate the side effects of proteasome inhibitors. One of failure may have been related to prehydration with normal saline.
the major motivations for the development of the second-generation Ixazomib may cause transient rash. Marizomib has been reported to
agents has been to reduce the occurrence of neuropathy. Unlike cause reversible CNS toxicities (hallucinations, loss of coordination).
IMiDs, proteasome inhibitors, as a class, do not appear to induce The toxicities of the newer agents will ultimately be important in
chromosomal abnormalities and therefore are not associated with an determining whether these drugs are suitable for first-line use.
increased risk for secondary malignancies. Proteasome inhibitors may
therefore be safer for long-term use/maintenance therapy than other
agents. Targeting Apoptosis Signaling in
(see Table 57.2). Hematologic Malignancies

The processes of cell division and cell death are tightly coupled so
Peripheral Neuropathy that a net increase in cell numbers does not occur. Alterations in the
expression or function of the genes controlling cell division and cell
The peripheral neuropathy associated with bortezomib is typically a death can upset this delicate balance and are hallmarks of cancer.
sensory neuropathy affecting the hands and feet in a “stocking and Although conventional anticancer drugs cause cell cycle perturbation